Pleomorphic liposarcoma (PLS )is a rare and aggressive, fast-growing tumor and high-grade malignancy with high recurrence, poor prognosis, and its treatment is still highly controversial. A rare, fast-growing type of cancer that begins in fat cells. It usually forms in the deep soft tissues of the arms or legs, but it may also form in the abdomen or chest. Pleomorphic liposarcoma often recurs (comes back) after treatment and spreads to other parts of the body, including the lungs.
Pleomorphic liposarcoma is characterized as the growth of a progressively painless mass, and it is easily ignored until the mass is big enough or there are some other compressive manifestations. It is known that this neoplasm is usually aggressive, occurring in adulthood, and usually in the limbs. Pleomorphic liposarcoma can occur in the mediastinum, liver, orbit, paratesticular region, and also as a purely dermal tumor [rx,rx,rx–rx]PLS could occur in various organs, but the most common sites are proximal extremities, especially in the lower extremities, and in other uncommon sites including the retroperitoneum, the abdominal wall, the chest wall, the mesentery, the pelvic cavity, the spermatic cord, the mediastinum, the parietal pleura, the pericardium, the foot, the spine, the head, and neck region.[rx,rx–rx]
Grading
According to the guidelines of the ADASP, pleomorphic liposarcoma is considered high grade
French Federation of Cancer Centers System grading scheme for adult sarcomas
- Tumor differentiation score = 3 for pleomorphic liposarcoma
- Mitotic index
- Score 1 0-9 mitoses per 10 hpf (0.1744 sq mm)
- Score 2 10-19 mitoses per 10 hpf
- Score 3 >19 mitoses per 10 hpf
- Tumor cell necrosis
- Score 0 No necrosis on any slide (one slide per 2 cm tumor diameter)
- Score 1 <50% of tumor is necrotic on slides examined
- Score 2 >50% of tumor is necrotic on slides examined
- Final Grade (add the three scores above)
- Grade 1 Sum of scores = 2 or 3
- Grade 2 Sum of scores = 4 or 5
- Grade 3 Sum of scores = 6 or more
Symptoms of Pleomorphic Liposarcoma
As previously mentioned, most patients are diagnosed with pleomorphic liposarcoma do not have any early symptoms and it can go unnoticed during the initial and primary stages of the disease until the tumor has grown to a large enough size to compress neighboring tissues and cause pain or decreased function.
- It can sometimes be noticed as a deep-seated mass to touch.
- Anorexia and abdominal distension, whereas the other patient had persistent pain in the left lower abdomen due to the compression from the pelvic tumor. However, these symptoms were ignored until the mass was big enough or there were some other serious manifestations.
- Pleomorphic liposarcoma, as with all other cancers, can present with non-specific symptoms such as fevers, chills, fatigue, night sweats, anorexia, and weight loss.
- If the tumor is retroperitoneal in location, it can present with specific symptoms in the abdomen, including abdominal pain, constipation, gastritis, or flank pain, swelling, and constipation, or the sensation of feeling full sooner than expected after eating.
- The well-differentiated type tumor is less aggressive and tends to be a large painless mass found in deeper tissues and in the retroperitoneum.
- Pleomorphic liposarcoma, round cell, and pleomorphic types tend to be in the arms and legs, whereas dedifferentiated tend to be in the retroperitoneum and often associated with the well-differentiated variety.
- Specifically, pleomorphic liposarcoma is the least common subtype with a high rate of recurrence and poor outcomes.
- Patients usually present with progressive dysphagia with weight loss
- A new or growing lump beneath your skin, especially around or behind your knees or on your thighs
- Pain or swelling
- Weakness in an arm or leg that has the lump
- Feeling full soon after you start eating
- A new lump anywhere on your body, or an existing lump that grows persistently
- Painful swelling or numbness in the area around your lump
- Blood in your stool, or black or tarry stool (an indication of blood)
- Blood in your vomit
- Abdominal pain or cramping
- Constipation
- Poop that has blood or looks black or tarry
- Cramping
- Bloody vomit
- Your belly gets larger
Tumors in the retroperitoneal, abdominal, and pelvic cavities were larger than those near the body surface such as the subcutaneous and intermuscular tissues.
Diagnosis of Pleomorphic Liposarcoma
Accessory examinations such as CT, ultrasound, and magnetic resonance imaging are critical for surgical methods by assessing the size of the tumor and the degree of tumor infiltration into the surrounding tissues. However, it is difficult to distinguish PLS/Pleomorphic liposarcoma from other liposarcoma and sarcoma using these accessory examinations. The definite diagnosis of PLS still depends on the pathological examination, which reveals highly meta topic cells with granular and/or foamy small vacuoles in cytoplasm, mono-/poly-nuclear giant cells with a deep
- Well circumscribed but non-encapsulated with infiltrative borders
- At least focal typical liposarcomatous areas
- Pleomorphic cells cover > 65% of cut surface with MFH-like, round cell liposarcoma-like (without vascular network), spindle cell liposarcoma-like or epithelioid cells (Mod Pathol 1999;12:722)
- Usually high grade with an enlarged round to bizarre nuclei
- Tumor necrosis common
- Median 25 mitotic figures / 10 HPF
- May have neutrophils within giant cells, hemangiopericytoma foci, extra- and intracellular hyaline droplets
- Epithelioid variant often confused with carcinoma
Imaging
- CT scan, magnetic resonance imaging (MRI) – If you have symptoms of MRCLS, your doctor will use imaging scans such as CT and MRI to look at where the tumor is and how big it is. They will also check for signs that the tumor has spread to other parts of the body. Although none of these techniques is specific, CT scan and MRI can be more helpful in narrowing down the differential diagnosis as both modalities can detect the percentage of a lipomatous/Pleomorphic liposarcoma component of the tumor. Higher fat content is associated with benign lipoma, while less fat is consistent with atypical lipoma or sarcoma. A definitive diagnosis can only be achieved by tissue examination. And in the majority of the cases, complete resection of the tumor is needed for a correct diagnosis [rx].
- Removing a sample of tissue for testing – During a biopsy procedure, your doctor removes a small sample of tissue to test for cancer cells. Your tumor’s location determines how the tissue sample is removed.
- Using advanced lab tests to determine the kinds of cells involved in cancer – Doctors who specialize in analyzing blood and body tissue (pathologists) will study your biopsy samples using specialized laboratory tests, such as immunohistochemistry, cytogenetic analysis, fluorescence in situ hybridization, and molecular genetic testing. These tests provide information about pleomorphic liposarcoma that helps your doctor determine your prognosis and your treatment options.
- Biopsy – To check if the tumor is MRCLS, your doctor will do a biopsy, taking a small sample from the tumor with a needle. An expert, called a pathologist, will study cells from the sample under the microscope to see what kind of tumor it is.
Treatment of Pleomorphic Liposarcoma
Treatments for pleomorphic liposarcoma include
- Surgery – The goal of surgery is to remove all of the cancer cells. Whenever possible, surgeons work to remove the entire pleomorphic liposarcoma. If a pleomorphic liposarcoma grows to involve nearby organs, removal of the entire pleomorphic liposarcoma may not be possible. In those situations, your doctor may recommend other treatments to shrink the liposarcoma to make it easier to remove during an operation.
- Radiation therapy – Radiation therapy uses powerful energy beams, such as X-rays and protons, to kill cancer cells. Radiation may be used after surgery to kill any cancer cells that remain. Radiation may also be used before surgery to shrink a tumor in order to make it more likely that surgeons can remove the entire tumor.
- Chemotherapy – Chemotherapy uses drugs to kill cancer cells. Not all types of pleomorphic liposarcoma are sensitive to chemotherapy drugs. Careful analysis of your cancer cells by an expert pathologist can determine whether chemotherapy is likely to help you. Chemotherapy may be used after surgery to kill any cancer cells that remain or before surgery to shrink a tumor. Chemotherapy is sometimes combined with radiation therapy.
Conventional chemotherapy pleomorphic liposarcoma is of low efficiency, so new drugs and target therapy might be good options. For example, eribulin and pazopanib are new treatment options for patients with metastatic STS.[rx,rx] Eribulin mesylate was reported to have selective activity in LPS.[rx] However, the adverse effects of eribulin were severe. In a phase III trial, treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin. Grade 3/4 adverse events were 152 (67%) who received eribulin.[rx] The Food and Drug Administration (FDA) approved pazopanib as second-line chemotherapy for the treatment of patients with advanced nonlipogenic STS, but still not yet for LPS.[rx] In addition, eribulin and pazopanib have not been approved for clinical use in China.
Meanwhile, antiangiogenic targeted drugs such as sunitinib, sorafenib, and pazopanib all appeared to demonstrate acceptable antitumor activity in liposarcomas.[rx–rx] Moreover, several articles reported that apatinib had a good effect on angiosarcoma[rx] and round cell liposarcoma.[rx]
Newer drugs for
Halaven® (eribulin) and Yondelis® (trabedectin) are approved for people who have not responded to earlier treatment, have widespread liposarcoma, or have cancers that cannot be removed via surgery.
Ongoing and Upcoming Clinical Trials of Targeted Therapy and Immunotherapy for Liposarcoma
| Drug Name/Code | Targets | Pathological subtypes of liposarcoma | Recruitment | Phase | ClinicalTrials. gov ID |
|---|---|---|---|---|---|
| APX005M | CD40 | Well/Dedifferentiated liposarcoma | Not yet recruiting | II | NCT03719430 |
| Ribociclib/LEE011 | CDK4/6 | All | Recruiting | Ib | NCT03009201 |
| Abemaciclib | CDK4/6 | Dedifferentiated liposarcoma | Recruiting | II | NCT02846987 |
| Ribociclib/LEE011 | CDK4/6 | Well/Dedifferentiated liposarcoma | Recruiting | II | NCT03096912 |
| Ribociclib/LEE011+Everolimus | CDK4/6+mTOR | Dedifferentiated liposarcoma | Recruiting | II | NCT03114527 |
| Regorafenib | c-Kit, B-Raf, Raf-1, RET, VEGFR1-3, PDGFR β etc. | All | Recruiting | II | NCT02048371 |
| Sitravatinib/MGCD516 | c-Kit, PDGFR α-β, c-Met, Axl etc. | Well/Dedifferentiated liposarcoma | Recruiting | II | NCT02978859 |
| Selinexor/KPT-330 | CRM1 | Dedifferentiated liposarcoma | Recruiting | II/III | NCT02606461 |
| Selinexor/KPT-330+Ixazomib | CRM1+20S proteasome | Dedifferentiated liposarcoma | Not yet recruiting | I | NCT03880123 |
| Itacitinib/INCB39110 | Jak1 | Myxoid/round cell liposarcoma | Not yet recruiting | I | NCT03670069 |
| MAGE-A4ᶜ¹º³²T cells | MAGE-A4 | Myxoid/round cell liposarcoma | Recruiting | I | NCT03132922 |
| HDM201+Ribociclib/LEE011 | MDM2+CDK4/6 | Well/Dedifferentiated liposarcoma | Active, not recruiting | Ib/II | NCT02343172 |
| CD8+ NY-ESO-1-Specific T Cells+LV305±CMB305 | NY-ESO-1 | Myxoid liposarcoma | Recruiting | I | NCT03450122 |
| NYCE T Cells | NY-ESO-1 | Myxoid/round cell liposarcoma | Recruiting | I | NCT03399448 |
| CMB305±Atezolizumab | NY-ESO-1±PD-L1 | Myxoid/round cell liposarcoma | Active, not recruiting | II | NCT02609984 |
| NY-ESO-1ᶜ²⁵⁹T cells | NY-ESO-1 | Myxoid/round cell liposarcoma | Recruiting | II | NCT02992743 |
| Pembrolizumab | PD-1 | All | Not yet recruiting | II | NCT03899805 |
| Pembrolizumab | PD-1 | Myxoid/round cell liposarcoma | Recruiting | II | NCT03063632 |
| Nivolumab+Nab-rapamycin | PD-1+mTOR | All | Recruiting | Ib | NCT03190174 |
| Nivolumab±Ipilimumab | PD-1±CTLA-4 | Dedifferentiated liposarcoma of the retroperitoneum | Recruiting | II | NCT03307616 |
| Olaratumab | PDGFR α | All | Active, not recruiting | III | NCT02451943 |
| Olaratumab | PDGFR α | Myxoid/round cell, pleomorphic or dedifferentiated liposarcoma | Recruiting | II | NCT02584309 |
| Efatutazone | PPAR-γ | Myxoid liposarcoma | Active, not recruiting | II | NCT02249949 |
| Pazopanib | VEGFR 1-3, c-Kit & PDGF-R | All | Recruiting | II | NCT01532687 |
| Pazopanib | VEGFR 1-3, c-Kit & PDGF-R | Dedifferentiated, or myxoid liposarcoma | Recruiting | II | NCT02357810 |
| Lenvatinib | VEGFR 2/3 | Dedifferentiated, myxoid, or pleomorphic liposarcoma |
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